Publications by authors named "Natarajan Kathiresan"

Type-II transmembrane serine proteases are effective pharmacological targets for host defence against viral entry and in certain cancer cell progressions. These serine proteases cleave viral spike proteins to expose the fusion peptide for cell entry, which is essential to the life cycle of the virus. TMPRSS2 inhibitors can also fight against respiratory viruses that employ them for cell entry.

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Our recent studies revealed the role of mouse Aprataxin PNK-like Factor (APLF) in development. Nevertheless, the comprehensive characterization of mouse APLF remains entirely unexplored. Based on domain deletion studies, here we report that mouse APLF's Acidic Domain and Fork Head Associated (FHA) domain can chaperone histones and repair DNA like the respective human orthologs.

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The continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the recent pandemic, has generated countless new variants with varying fitness. Mutations of the spike glycoprotein play a particularly vital role in shaping its evolutionary trajectory, as they have the capability to alter its infectivity and antigenicity. We present a time-resolved statistical method, Dynamic Expedition of Leading Mutations (deLemus), to analyze the evolutionary dynamics of the SARS-CoV-2 spike glycoprotein.

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Spike glycoprotein has a significant role in the entry of SARS-CoV-2 to host cells, which makes it a potential drug target. Continued accumulation of non-synonymous mutations in the receptor binding domain of spike protein poses great challenges in identifying antiviral drugs targeting this protein. This study aims to identify potential entry inhibitors of SARS-CoV-2 using virtual screening and molecular dynamics (MD) simulations from three distinct chemical libraries including Pandemic Response Box, Drugbank and DrugCentral, comprising 6971 small molecules.

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Background And Purpose: α4β2 nicotinic acetylcholine (nACh) receptors assemble in two stoichiometric forms, one of which is potentiated by calcium. The sites of calcium binding that underpin potentiation are not known.

Experimental Approach: To identify calcium binding sites, we applied cryo-electron microscopy (cryo-EM) and molecular dynamics (MD) simulations to each stoichiometric form of the α4β2 nACh receptor in the presence of calcium ions.

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Mechanisms behind the fluctuations in the ionic current through single acetylcholine receptor (AChR) channels have remained elusive. In a recent study of muscle AChR we showed that mutation of a conserved intramembrane salt bridge in the β- and δ-subunits markedly increased fluctuations in the open channel current that extended from low to high frequency. Here, we show that extracellular divalent cations reduce the high-frequency fluctuations and increase the low-frequency fluctuations.

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RNA 3'-end polyadenylation that marks transcripts for degradation is implicated in general stress response in Yet, the mechanism and regulation of poly(A) polymerase I (PAPI) in stress response are obscure. We show that (that encodes PAPI)-null mutation widely stabilises stress response mRNAs and imparts cellular tolerance to multiple stresses, whereas PAPI ectopic expression renders cells stress-sensitive. We demonstrate that there is a substantial loss of PAPI activity on stress exposure that functionally phenocopies -null mutation stabilising target mRNAs.

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The mainstream approach to antiviral drugs against COVID-19 is to focus on key stages of the SARS-CoV-2 life cycle. The vast majority of candidates under investigation are repurposed from agents of other indications. Understanding protein-inhibitor interactions at the molecular scale will provide crucial insights for drug discovery to stop this pandemic.

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The α7 nicotinic acetylcholine receptor (nAChR) is among the most abundant types of nAChR in the brain, yet the ability of nerve-released ACh to activate α7 remains enigmatic. In particular, a major population of α7 resides in extra-synaptic regions where the ACh concentration is reduced, owing to dilution and enzymatic hydrolysis, yet ACh shows low potency in activating α7. Using high-resolution single-channel recording techniques, we show that extracellular calcium is a powerful potentiator of α7 activated by low concentrations of ACh.

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During platelet biogenesis, microtubules (MTs) are arranged into submembranous structures (the marginal band) that encircle the cell in a single plane. This unique MT array has no equivalent in any other mammalian cell, and the mechanisms responsible for this particular mode of assembly are not fully understood. One possibility is that platelet MTs are composed of a particular set of tubulin isotypes that carry specific posttranslational modifications.

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Article Synopsis
  • Scientists found out that three new gene changes can cause a problem called thyroid dysgenesis (TD), which affects how the thyroid works.
  • These changes were discovered in three families and are pretty rare, making up only 1.1% of the mutated cases studied.
  • The research shows that these gene changes can mess up the thyroid's ability to grow and release important hormones, and they also affect how blood platelets work, which can lead to other health issues.
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Brain development involves extensive migration of neurons. Microtubules (MTs) are key cellular effectors of neuronal displacement that are assembled from α/β-tubulin heterodimers. Mutation of the α-tubulin isotype TUBA1A is associated with cortical malformations in humans.

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Posttranslational modifications of tubulin currently emerge as key regulators of microtubule functions. Polyglutamylation generates a variety of modification patterns that are essential for controlling microtubule functions in different cell types and organelles, and deregulation of these patterns has been linked to ciliopathies, cancer and neurodegeneration. How the different glutamylating enzymes determine precise modification patterns has so far remained elusive.

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Microtubules are key cytoskeletal elements of all eukaryotic cells and are assembled of evolutionarily conserved α-tubulin-β-tubulin heterodimers. Despite their uniform structure, microtubules fulfill a large diversity of functions. A regulatory mechanism to control the specialization of the microtubule cytoskeleton is the 'tubulin code', which is generated by (i) expression of different α- and β-tubulin isotypes, and by (ii) post-translational modifications of tubulin.

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Across different cell types and tissues, microtubules are assembled from highly conserved dimers of α- and β-tubulin. Despite their highly similar structures, microtubules have functional heterogeneity, generated either by the expression of different tubulin genes, encoding distinct isotypes, or by posttranslational modifications of tubulin. This genetically encoded and posttranslational generated heterogeneity of tubulin-the "tubulin code"-has the potential to modulate microtubule structure, dynamics, and interactions with associated proteins.

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The mechanism of nucleotide-regulated assembly and disassembly of the prokaryotic cell division protein FtsZ is not yet clearly understood. In this work, we attempt to characterize the functional motions in monomeric FtsZ through molecular dynamics simulations and essential dynamics (ED) analyses and correlate those motions to FtsZ assembly and disassembly. Results suggest that the nucleotide binding subdomain of FtsZ can switch between multitudes of curved conformations in all nucleotide states, but it prefers to be in an assembly competent less curved conformation in the GTP-bound state.

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The complex dynamic behavior of microtubules (MTs) is believed to be primarily due to the αβ-tubulin dimer architecture and its intrinsic GTPase activity. Hence, a detailed knowledge of the conformational variations of isolated α-GTP-β-GTP- and α-GTP-β-GDP-tubulin dimers in solution and their implications to interdimer interactions and stability is directly relevant to understand the MT dynamics. An attempt has been made here by combining molecular dynamics (MD) simulations and protein-protein docking studies that unravels key structural features of tubulin dimer in different nucleotide states and correlates their association to tubulin assembly.

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The vital role of tubulin dimer in cell division makes it an attractive drug target. Drugs that target tubulin showed significant clinical success in treating various cancers. However, the efficacy of these drugs is attenuated by the emergence of tubulin mutants that are unsusceptible to several classes of tubulin binding drugs.

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